title: EGFR ligands as pharmacodynamic biomarkers in metastatic colorectal cancer patients treated with cetuximab and irinotecan.
abstract: This study was conducted to describe the modulation of plasma epidermal growth factor receptor (EGFR) ligands in EGFR-positive metastatic colorectal cancer (mCRC) patients during treatment with cetuximab and irinotecan and to explore the clinical implication of plasma levels' variations as potential biomarkers of benefit. Plasma amphiregulin (AR), epidermal growth factor (EGF), transforming growth factor-α, and heparin binding-EGF were assessed by ELISA in 45 chemorefractory mCRC patients, treated with cetuximab and irinotecan. Plasma levels were measured before and 1 h after the first administration of cetuximab, before and 1 h after the second administration, and before the third and the fifth cycles. KRAS and BRAF mutational status were determined. EGFR ligands' levels were differently modulated according to tumor KRAS and BRAF mutational status. In KRAS wild-type patients (n = 34), AR and EGF early increased and higher increases were significantly associated with worse clinical outcome. By adopting a specific cut-off value, patients with higher levels of AR 1 h after the first administration had significantly worse response rate, progression free survival, and overall survival. This hypothesis-generating study shows that EGFR ligands are significantly modulated by cetuximab plus irinotecan according to KRAS and BRAF mutational status, and they warrant further investigation as pharmacodynamic markers of resistance to anti-EGFRs.
authors.affiliation: Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Istituto Toscano Tumori, Via Roma 67, 56126, Pisa, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.forename: Anna
authors.initials: A
authors.lastname: Fioravanti
authors.forename: Paola
authors.initials: P
authors.lastname: Orlandi
authors.forename: Lisa
authors.initials: L
authors.lastname: Salvatore
authors.forename: Gianluca
authors.initials: G
authors.lastname: Masi
authors.forename: Marta
authors.initials: M
authors.lastname: Schirripa
authors.forename: Teresa
authors.initials: T
authors.lastname: Di Desidero
authors.forename: Carlotta
authors.initials: C
authors.lastname: Antoniotti
authors.forename: Bastianina
authors.initials: B
authors.lastname: Canu
authors.forename: Pinuccia
authors.initials: P
authors.lastname: Faviana
authors.forename: Elisa
authors.initials: E
authors.lastname: Sensi
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lupi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
authors.forename: Fulvio
authors.initials: F
authors.lastname: Basolo
authors.forename: Antonello
authors.initials: A
authors.lastname: Di Paolo
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D008024:Ligands; D011518:Proto-Oncogene Proteins; D000077146:Irinotecan; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002166:Camptothecin